Complex Regional Pain Syndrome Type I (CRPS I) is a frequent sequela of distal tibia and radius fractures and limb surgery though it can occur even after minor injuries. Pain is a prominent feature of this syndrome, and disability in the setting of CRPS is very common. Recently our group described a tibia fracture model that exhibits the principal stigmata of CRPS I including chronic edema, allodynia, epidermal thickening, keratinocyte proliferation and periarticular osteoporosis. Unfortunately, the mechanisms supporting these changes remain highly enigmatic, and available clinical treatments have limited efficacy. Activation of the innate system of immunity in skin initiates the cascade of changes supporting this chronic disease. This research proposal outlines a vertically integrated set of experiments all focused on the central hypothesis that neural activation of keratinocyte inflammasomes is required for the production of IL-12, downstream mediators such as nerve growth factor (NGF), and ultimately the development of CRPS-like features in our rodent model. The project's specific aims are as follows: 1. We will test the hypothesis that substance P (SP), calcitonin gene related peptide (CGRP) and beta 2 adrenergic receptor agonists stimulate the production of key inflammasome components, and the activation of caspase-1 resulting in enhanced cytokine production. 2. We will test the hypothesis that inflammasome activation occurs after fracture, and is required for expression of the CRPS-like syndrome after tibial fracture in mice. 3. We will test the hypothesis that intact peripheral nervous system signaling is required for the activation of inflammasomes in skin after fracture, and that this activation is, in turn, required for the expression of CRPS-related biomarkers as well as edema, warmth and nociceptive sensitization. These experiments will use both cell culture and whole animal experiments. We will measure gene expression, mediator levels, enzymatic activity and behavioral indices of CRPS. In the short term we will refine the model of neuro-cutaneous signaling as it supports specific dimensions of CRPS I. In the longer run we hope to translate these findings into clinical trials involving CRPS I patients which will be made possible by the clinical orientation of the investigative team and the advent of pharmaceutical agents targeted at the regulation of inflammation.